THE IMPACT OF METALLOESTROGENS ON THE PHYSIOLOGY OF MALE REPRODUCTIVE HEALTH AS A CURRENT PROBLEM OF THE XXI CENTURY
INTRODUCTION
Over the last decades, in highly developed countries, a visible trend of birth rate reduction is observed. One of the causes of this negative phenomenom is the observed progression in the reduction of male reproductive potential. Male infertility can result from many different agents, such as: anatomical or genetic abnormalities, systemic or neurological diseases, infections, trauma, iatrogenic injury, gonadotoxins and the development of sperm antibodies, lifestyle (especially obesity, heat and tobacco smoking) and environmental factors (1-3). Current epidemiological studies especially indicate a deterioration of semen parameters in recent years: a reduction in volume, sperm count and mobility, and changes in morphology (4, 5). The World Health Organization (WHO) has reported (1980, 1987, 1992, 1999 and 2010) on deteriorating values of semen parameters in the population, and male infertility has become a civilizational disease of the XXIst century (6-8) (Table 1). Moreover, there is a large percentage of normozoospermic men (physiological values of standard semen analysis) with idiopathic infertility. The first long-term meta-analysis was conducted by Carlsen et al. (9), who analysed this problem in detail and published the results of their study in 1992. This study documented significantly decreased semen parameters such as sperm count and seminal volume of about 41% and 19%, respectively, over 50 years of observation (from 1940-990). Since then, many studies have been published comparing the quality of semen in various countries. For example, a retrospective and descriptive study conducted in France showed a decrease in sperm concentration of about 32% over the period 1989 – 2005. Additionally, a significant, but not quantifiable, decrease in the percentage of sperm with morphologically normal forms was observed (10). There was also a reduction in semen volume (43%) in men aged 35 – 50, which constitutes an approximate 32% decline in sperm counts and an overall 57% diminution in mean sperm concentration in different geographical regions of the world (11, 12). The increased number of cases of cryptorchidism and hypospadias is also a serious problem (13). Additionally disturbances in plasma prooxidant/antioxidant balance parameters (e.g. melatonin, advanced oxidation protein products (AOPP), total antioxidant capacity (TAC) as well as proteases/inhibitors balance parameters (e.g. metalloproteinases MMP-2 and MMP-9, and their inhibitors - TIMP-1 and TIMP-2) are indicated as important element affecting the semen condition and their mutual relationships will be interesting aspect of future studies (14).
It should be underlined that adverse changes in male fertility may also be associated with environmental exposure to different substances, especially endocrine active xenobiotics, which are capable of disturbing endocrine homeostasis in the organism. They are known as xenoestrogens (XEs), and also known as endocrine disruptors (EDCs) (15). The endocrine active substances significantly affecting the male reproductive system, also known as endocrine disruptors, could be xenoestrogens or xenoandrogens (16, 17). Over the last few years, more and more evidence indicates the influence of XEs derived from different sources (e.g. diet, environmental pollution, tobacco smoke, cosmetics), which seems to be crucial in the development of male infertility (18-20). They can definitely reduce the reproductive potential of men, acting mainly by disrupting the endocrine hormonal system at certain doses, as well as participating in carcinogenesis of endocrine target tissues (21). The unfavorable influence of endocrine disruptors on the physiology of male fertility is indicated by epidemiological studies, which suggest that male fertility disorders occur mainly in developed countries (22, 23). Exogenous estrogens are highly heterogeneous in structure and include synthetic organic compounds such as pesticides and plastics, as well as natural plant-derived xenoestrogens, i.e. phytoestrogens. The role and mechanisms of action of many XEs belonging to different groups of chemicals are rather well known and well described, but relatively little information applies to metal ions acting as EDCs. Such groups of metal ions with “estrogenic activity” are called metalloestrogens (MEs) (24, 25). The group of metalloestrogens includes: aluminum (Al), antimony (Sb), arsenic (As), barium (Ba), cadmium (Cd), chromium (Cr), cobalt (Co), copper (Cu), lead (Pb), mercury (Hg), molibdenium (Mo), nickel (Ni), selenium (Se) tin (Sn), and vanadium (V). Most of these metals, especially those referred to as ‘heavy metals’, are toxic for wildlife, experimental animals, and humans. Many experimental studies, especially those derived from recent years, on animals and humans occupationally or environmentally exposed to some of these heavy metals, show their negative impact on the physiology of reproductive health (26-31). Information on the effects of other metals and transition metals on male reproductive outcomes is limited, however it is documented that most of the ions of these metals may influence estrogen receptor (ERs) function, and are capable of binding to cellular estrogen receptors and then mimicking the action of physiological estrogens (22-33). They can significantly modulate the hormonal status of the organism and finally induce many disturbances in human organism homeostasis (33-35). A scheme illustrating the influence of metals in air pollution, drinking water and food on male fertility is shown on Fig. 1. The role of some MEs in cancerogenesis, both in women (e.g. breast or endometrium cancer) and men (e.g. testicular or prostate cancer) is known and particularly well proven in women (36-39), but still little is known about their role in the regulation of male reproductive potential, therefore we decided to analyse the available information exploring this problem.
The aim of this review is completion of the available information about the role and mechanisms of metalloestrogen action in the human organism and their influence on the physiology of male reproductive health, according to the current state of knowledge. In our review we have also included the results of investigations based on animal models and cellular research to better characterize the topic discussed, since the investigations provided e.g. on animal models reflect changes which can also be observed in humans. On the other hand the availability of information about xenoestrogen action is higher for e.g. animal models, than humans. The role of certain metals analysed in the context of their influence on male fertility is still poorly investigated, and for some of them only single studies are available. We decided to describe first the most important and well-investigated alphabetically, and then all of the lesser known together.
Our review is based on literature research, using the PubMed and GoogleScholar databases, including recent data which were published from 2000 onward in this review, mostly in English, using the search terms, or their combination: xenoestrogens, metalloestrogens, aluminum, antimony, arsenic, barium, cadmium, chromium, molibdenium, mercury, lead, cobalt, copper, nickel, selenium, tin, vanadium, male fertility, semen quality, male reproductive potential, mechanisms of metalloestrogen action, environmental pollution. The study included research on human and some animal and cell models. Finally, 194 items from original papers and reviews were selected, which in our opinion seemed to be the most useful and fitting regarding this issue.
THE ROLE OF ESTROGENS IN THE MALE REPRODUCTIVE TRACT
Although estrogens are primarily the main female sex hormones, they also play an important role in the male reproductive system. For example, their participation has currently been documented in the normal course of spermatogenesis, as well as in other aspects of male fertility. Increasingly, it is pointed out that in men exposed to xenoestrogens, disruption of the natural estrogen-androgen balance is observed, which adversely affects the reproductive health of men (40). The results of some studies have shown suppressed spermatogenesis and the development of Sertoli and Leydig cells in animals exposed to xenoestrogens (22). Exposure to environmental estrogens during fetal life seems to be the most significant, because the proliferation of Sertoli cells are growing at this time (16, 41, 42). Xenoestrogens inhibit the secretion of a follicle-stimulating hormone (FSH) that affects the proliferation, maturation and function of the supporting Sertoli cells that produce regulatory signals and nutrients for the maintenance of developing germ cells. A smaller number of these cells results in reduced mice semen production during the reproductive period (43, 44). These irreversible changes also occur in humans, as is confirmed by studies of men with hypogonadism (45). Despite the administration of gonadotropins, the expected effects were not obtained, which indicates a lack of adequate Sertoli cells, which were formed only in the perinatal period (42, 44).
Information about estrogens and their metabolites, and mechanisms of action on the estrogen receptors and cell metabolism have been given in detail in the literature (25, 46). Briefly, 17β-estradiol (E2) is mainly formed in peripheral tissues from testosterone (T) in an enzymatic reaction with the participation of aromatase. It is produced in the adipose tissue, brain and adrenal glands, as well by the Sertoli, Leydig and spermatogenic cells (25, 47). Production of E2 in the testicles was confirmed after the administration of human chorionic gonadotropin (HCG), when after 24 h the estrogen ejection was observed to be faster than the testosterone. HCG acts like the luteinizing hormone (LH) - it induces T synthesis in the Leydig cells (48). The presence of estrogen receptors in men has been demonstrated in many tissues, which indicates their significant role in the regulation of various physiological processes: the formation of bones, inhibition of growth, lipid metabolism etc. E2 also regulates the function of the testicles by affecting the proliferation of Leydig and Sertoli cells (47, 49). In vitro studies have demonstrated the protective effect of estrogens on spermatozooa by preventing their apoptosis, and have been shown to increase the number of gonocytes. This view has been confirmed by studies in estrogen receptor knockout mice - deprived of estrogen receptors. These mice, despite well-developed reproductive systems at the end of the puberty process, gradually observed the disappearance of sperm production (48, 50). As a cause of infertility, the occurrence of increased pressure inside the epididymal canal as a result of abnormal drainage of the fluid within the epididymal canal, is indicated. Estrogen action is required for fertility in male mice, and mutation of the estrogen receptors (ER) in ERKO males (male mice with disrupted ER genes) leads to reduced mating frequency, low sperm numbers and defective sperm function. Estrogens were also recognized as factors initiating the process of spermatogenesis during puberty. Moreover, estrogen interacts with FSH enhancing its stimulating effect on spermatogenesis (51). It is indicated that some metalloestrogens can influence the steroid synthesis of sex hormones, accumulation in the male reproductive tract and the activation of estrogen receptors (52).
XENOSTROGENS AND METALLOESTROGENS AND THEIR MECHANISMS OF ACTION
As was mentioned above, xenoestrogens are exogenous compounds with a diverse chemical structure commonly present in the environment. Their common feature is an estrogen-like action, but they show estrogenic effects through various mechanisms. Xenoestrogens and their effects are widely discussed, particularly in relation to human reproductive health, but lately also with reference to male infertility problems (22, 53). Every compound from the EDC group is characterized by a specific mechanism of action. Due to the fact that many exogenous compounds have an analogous structure to natural hormones, the direct interaction of EDCs with the estrogen receptor located in the nucleus, by binding to the ligand binding domain (LBD) present in the ER structure, is indicated as the most common and important. It leads to stimulation (agonism) or inhibition (antagonism) of its transcriptional activity, disturbing the physiological function of cells and hormonal homeostasis of the organism (24, 54, 55).
In the second most important place among EDC actions with ER, especially without a structure similar to the receptor, is the area of so-called ‘zinc fingers’ in the DNA binding domain (DBD). These EDCs can displace zinc ions, replacing them in DBD, having an effect on the receptor structure and influencing the pathways of intracellular signal transduction, interaction with DNA and target gene expression (56).
The next possible mechanism, disorders in the synthesis of estrogen receptors a (ERα) in Leydig cells and influence on mRNA levels of steroidogenic acute regulatory protein (StAR) is described (57, 58). The disturbances (stimulation or inhibition) in the synthesis, metabolism or degradation of endogenous hormones, especially testosterone production, by affecting the activity of the synthesis and metabolism of Δ-5-3-β-hydroxysteroid dehydrogenase (3β-HSD), 17β-hydroxysteroid dehydrogenase (17β-HSD), CYP11A and CYP17A and aromatase, can be observed. It was documented that in general a number of signaling and regulatory pathways have been demonstrated as influencing 3β-HSD transcription and activity (57-59).
The next important mechanism among EDC actions is the modulation of the bioavailability of sex hormones (e.g. by limiting the concentration of sex hormone binding globulin (SHBG)). Stimulation or inhibition of endogenous hormone binding protein leading to decreased or enhanced circulating hormone availability is also observed (58). SHBG, in addition to the binding of androgens and estrogens, also has an affinity for EDC binding, among others: phthalate esters. This leads to an increased amount of free hormones in the circulation, and as a result, endocrine disorders (24, 54, 60). Some authors indicated on the high levels of soluble vascular endothelial growth factor receptor 1 (sFlt-1) and low levels of vascular endothelial growth factor (VEGF) in follicular fluid as possible predictive factor of the ovarian hyperstimulation syndrome (OHSS) in women (61). Probably it will be also interesting point of research of potential role of VEGF and sFlt-1 in male infertility in the aspect of changes of vascular permeability.
The hypothalamic-pituitary-testicular (HPT) axis is described as the last mechanism of endocrine disruption. The HPT is responsible for the proper functioning of the testicles and maintains the appropriate level of T, responsible for the spermatogenesis process in the testes, by the use of a negative feedback mechanism. Pulse secretion of gonadotropin-releasing hormone (GnRH) stimulates the secretion of FSH and LH, which in turn stimulates testosterone synthesis in Leydig cells, thereby regulating spermatogenesis in Sertoli cells (62). High concentrations of T inhibit GnRH secretion. EDCs may interfere with the function of the HPT by interacting with receptors for LH, FSH or GnRH. Moreover, metalloestrogens may disrupt Ca2+ flux, which is part of the cAMP cascade, interfering with the transduction of the signal after the stimulation of G protein-coupled receptors (GPR), including LH/hCGR (63). The grip point for EDCs (e.g. lead) can also be enzymes: cAMP dependent protein kinase A or inositol triphosphate dependent protein kinase C, also participating in the signaling pathway activating GPR. It was also shown that some EDCs reduce the expression of mRNA for hypothalamic kisspeptin (Kiss-1). Kiss-1 and its GPR54 receptor controls the secretion of GnRH and the activation of the pituitary-hypothalamic-testes axis (64).
The chemical structure of xenoestrogens is diverse, they have been mainly organic, in particular phenolic or carbon ring structures of varying structural complexity (65). Lastly, more and more scientific research concerns certain metal ions. With respect to metalloestrogens, which are inorganic compounds, the indicated mechanism of action is somewhat different. This applies either to a direct effect on the estrogen receptors or indirectly on the induction or intensification of oxidative stress (OS), and hence secondary disorders caused by OS (66). Additionally, influence on the regulation of gene expression and the function of signal transduction pathways in a cell, including the pathway dependent on estrogen receptors, is also indicated (16, 24). But these mechanisms have not been fully investigated or described yet.
Estrogen receptors are located in the nucleus of target tissue and cells and consist of fragments called domains. The two main types of ERs occur in the human organism, estrogen receptors a and b (ERa and ERb, respectively). Their distribution in tissues and affinities both to endo- and exogenous estrogens are different (67). In men they occur both in cells of the reproductive system as well as in others, e.g. osteoclasts and muscle cells. Estrogens, acting on target tissues through estrogen receptors, not only regulate the function of the male reproductive system, but also affect its development (56). Study conducted in animal model with seasonal changes in the intratesticular sex hormones level revealed interesting association between the ERs expression and Leydig cells function and architecture depending on these seasonal changes of endogenous estrogen status in the testis, with insight into mechanism of control of animal Leydig cells. Ultrastructure analysis revealed alterations in mitochondria number as well as endoplasmic reticulum and Golgi complexes volume and structure in these cells, especially after ERa blockage by specific inhibitor. Additionally diverse and complex ERs regulation at mRNA level and protein expression of some steroidogenic and secretory molecules were revealed in relations to endogenous estrogen level in treated males. It was to varying degrees related to a cycle of seasonal changes in the intratesticular sex hormones level (68).
Xenoestrogens, which are able to induce much deterioration in the male reproductive system, act similarly (69). The most important part of the estrogen receptor is the structural DNA-binding domain (DBD) with two zinc finger motifs distinguished, and this element is indicated as the main mechanism of xenoestrogens and also metalloestrogens action (70). These structures are formed (usually) from 30 to 40 amino acids, and spatial organization of these domains is stabilized by coordinating bonds formed between zinc ion and cystein thiol groups and/or imidazole histidines (71). Interaction with the ERs by the zinc finger in the DBD receptors’ domain, disrupting receptor interaction with the DNA and target genes, is indicated. The molecular mechanism of xenoestrogens action consists mainly of replacing the zinc ions by finger motifs in the receptor DBD domain. This causes weakening or inhibition of receptor binding to the DNA of the target gene (72). Some of the metal ions may also interact with other receptor regions, for example cadmium can react with ligand-binding domain (LBD), blocking the attachment of the appropriate ligand (i.e. estradiol) to the receptor (33, 73). Others can increase cell response to estrogens, which results in excessive proliferation and growth of cells (74). The receptor mechanism has been further investigated, for example for cadmium, aluminum and chromium (75). The mechanisms of action of other metals is mainly related to reactive oxygen species (ROS) generation and induction of oxidative stress or inflammatory response (33, 68). The scheme of the mechanisms of xenoestrogens action on male fertility is presented in Fig. 2.
Metalloestrogens may affect fertility through direct effects on the reproductive organs, but also through the endocrine system. They have the ability to crawl and damage the prostate, epididymis and semen. They can also cause damage to sperm DNA by reducing the stability of chromatin. Damage to the Sertoli cells during fetal life causes an irreversible effect (the number of Sertoli cells determines the amount of sperm produced - they can perform their functions for a limited number of germ cells). Sertolli cells proliferate in neonatal, fetal and pre-pubertal-periods (when high sensitivity to metal ions occurs) (16, 42).
METAL IONS AS METALLOESTROGENS AND THEIR ROLE IN MALE FERTILITY
Aluminium
Aluminum (Al) is a natural element in the environment, primarily in the Earth’s crust (76). It is widespread, and distributed in various industries, including the cosmetics industry, mainly as an antiperspirant ingredient (77). Aluminium compounds are used in pharmaceuticals and in water treatment processes (78). The relationship between aluminum exposure and morbidity in breast cancer or neurodegenerative diseases has been proven (79, 80). It has been shown that the main mechanism of this influence is aluminum activity as an endocrine disruptor, in the main manner characteristic for metals and described above (81). Additionally the induction of ROS production by aluminium ions as a mechanism of reproductive toxicity is indicated (82).
Some authors have pointed to the possibility of aluminum influencing the processes of maturation and the production of sperm and its storage in the epididymis, which results in a reduction in sperm count. This was histologically confirmed in Wistar rats which received orally aluminium chloride (from 475 to 1900 mg/kg b.w.) with distilled water. Aluminium showed marked distorted seminiferous tubules with loss of normal distribution of epithelial linning and vacuolar cytoplasm (78). In studies conducted on 3 generations (F1, F2, F3 - first, second, third filial generation, respectively) of male Wistar rats, whose parents (F0 generation) were exposed to aluminium sulphate (from 200 to 1000 ppb, wather solutions) for six months, a significant reduction of serum testosterone levels was noticed in all examined groups, compared to the control one (not exposed). Significantly lower T concentrations in F1 and F2 than in the F0 generation was connected with LH fluctuations in F0 and a significant LH decrease in F2 and F3 generation. Testes weight decrease, increased number of immobile and abnormal sperm, and histoarchitecture alterations in the testes were observed. In all generations, a greater amount of immobile and abnormal sperm in comparison to the control was also observed when comparing the F0 generation with F1 and F2, and a statistically significant reduction in testes weight in subsequent generations was also observed, which confirms that chronic exposure to aluminium was significantly deleterious (27). In other animal studies, used doses of Al (exposure period 60 days) were similar to those found in the human diet (8.3 mg/kg b.w./day). A significant reduction in sperm parameters such as motility, sperm counts and viability and a higher percentage of abnormal sperm and impaired testes histology, even at low exposure (5 mg/kg b.w./day) as well as in high doses of aluminium (8.3 mg/kg b.w./day), were observed. The authors also confirmed increased oxidative stress in reproductive organs and inflammation in the testes under aluminium exposure (83). Similar results were obtained by Mouro et al. (84) in studies on an animal model, further noting the dose-dependent effect. The authors revealed that the consequences of exposure to even low levels of Al were as negative as high levels on reproductive parameters, suggesting an adverse impact on male fertility in the concentrations tolerated in drinking water, established by international organizations as 3.35 × 10–4 mg/kg. They observed negative impacts on serum T levels, testicular histomorphometry and sperm parameters. Yousef et al. (85) also revealed a significantly decreased number of motile and viable rabbit sperm after AlCl3 treatment (10, 15 and 20 mM). The response was both Al concentration and time dependent, as well as enhancing free radical generation and alterations in the activities of many enzymes: a decrease in superoxide dismutase (SOD), catalase (CAT) and acid phosphatase (AP), and an increase in aspartate transaminase (AST) and alanine transaminase (ALT). Additionally, the authors revealed the protective effects of antioxidants (vitamins C and E) against the cytotoxicity induced by AlCl3. Zatta et al. (86) analysed the effect of aluminum on aconitase protein in rats, which shows a significant decrease in the activity of this enzyme. Akonitase is a citrate-binding protein in the Krebs cycle, so decreasing its activity may result in reduced Krebs cycle performance and adversely affect the mitochondria, which may be a potential cause of sperm injury - decreased motility and viability. The studies of Klein et al. (87) on human semen show the presence of aluminum in sperm, especially in men with oligozoospermia, where statistically significant higher concentrations of aluminum were observed. Statistical significance was not observed after analysis of other semen parameters. However, these studies have shown that aluminum may have a detrimental effect on spermatogenesis in humans as well (87).
Arsenic
Arsenic (As) is a metal widely present in the environment, and one of the main sources of exposure is contaminated water and food (88). Toxicity to humans shows As(III) and As(V). Arsenic, like chromium, is an agent that induces oxidative stress, which is indicated as the main route of its unfavorable action (89). Because of its huge prevalence in the environment, potential for human exposure, and the magnitude and severity of the health problems it causes, the United States Agency for Toxic Substances and Disease Registry (ATSDR) has ranked arsenic as No. 1 on its Priority List of Hazardous Substances for many years. Arsenic is classified by the International Agency for Research on Cancer (IARC) as a potent human carcinogen (88, 90, 91). Chronic exposure to elevated concentrations of As has also been associated with an increased risk of a number of noncancerous effects (91). Although the adverse health effects arising from exposure to arsenic are well-recognized, the mechanism of action responsible for the diverse range of health effects is complicated and still poorly understood (93, 94).
It has been shown that high doses of arsenic in the form of inorganic salts induces apoptosis by activating enzymes participating in hydrogen peroxide production (e.g. nicotinamideadenine dinucleotide phosphate (NADH)). The H2O2 is secreted by macrophages associated with Leydig cells in the interstitium of the testes and therefore can negatively affect sperm quality in men. It is believed that the harmful effect of arsenic on fertility is caused by impaired T synthesis in the testes, and reduction of testes weight and accessory sex organs, as well as morphological changes in sperm and a decrease in their amount, hence impaired spermatogenesis. Induction of apoptosis is probably also associated with a reduction of mitochondrial membrane redox potential, and consequently the release of cytochrome C into the cytosol, the induction of caspase 3, and as a result DNA chain fragmentation (95). Additionally it is believed that inorganic arsenate as a molecular analogue of phosphate can compete for phosphate anion transporters and replace phosphate in some biochemical reactions (e.g. generation of ATP, during oxidative phosphorylation). As another important aspect of As action, its high affinity to thiol groups of many proteins is indicated. It is connected with numerous disturbances of chromatin proteins and spermatozoa flagella, as well as enzymes. The capability of binding trivalent arsenicals to cysteine residues in zinc fingers in different receptors and direct binding of pentavalent arsenicals to protein is indicated as one of the possible ways of action (96).
It is indicated that high arsenic level may suppress the sensitivity of gonadotropic cells to gonadotropin-releasing hormones, as well as gonadotropin secretion by elevating plasma levels of glucocorticoids. These lead to the development of gonad toxicity in animals and cause reduction in sperm number, viability and motility (89). Ferreira et al. (97), in mice exposed orally to sodium arsenite (NaAsO2) for a period of 35 days (a full cycle of spermatogenesis in mice), observed a significant reduction in testicular mass (expressed as testes/body weight ratio) compared to the control group (animals that did not receive arsenic in their drinking water). Additionally, excessive exfoliation of immature germ cells was observed in the lumen of seminal tubules. Significant damage to the epithelium and the presence of numerous intraepithelial vacuoles and reduced motility of sperm were noted. Additionally, a massive degeneration of germ cells, and alterations in the levels of LH, FSH and T were also reported (89). Disorders of spermatogenesis by arsenic may also be related to its inhibitory effect on T, LH and FSH secretion by different varieties of germ cells in the stage VII seminiferous epithelium cycle, as was noted by Sarkar et al. (98) in rats during 26 days of intraperitoneally administrated sodium arsenite (at doses of 4 – 6 mg/kg/day). Histological examination of arsenic-treated Swiss albino mice testes revealed a highly significant depletion in all the germ cell populations such as spermatogonia A and B, primary and secondary spermatocytes, as well as spermatids with respect to controls (99). Li et al. (100) revealed significant negative correlations between the concentrations of As, as well as Cu and Pb, and sperm concentrations. Moreover, they observed that Cu, Mn, and Se concentrations were significantly higher in the infertile men than in the healthy subjects. These findings provide evidence for relationships between human semen quality and metal exposures (100). A substantial number of some environmental pollutants, such as heavy metals (arsenic, cadmium, lead, mercury), have been shown to disrupt endocrine function, and they can cause reproductive problems by decreasing sperm count and quality, increasing the number of testicular germ cells and causing male breast cancer, cryptorchidism, hypospadias, miscarriages, endometriosis, impaired fertility, irregularities of the menstrual cycle, and infertility (101).
Cadmium
Cadmium (Cd) is a naturally occurring toxic heavy metal that has a significant degree of accumulation in the organism. Target organs are kidneys, liver, bones and male reproductive organs, but Cd has also been shown to possess the ability to accumulate in the hypothalamus and pituitary gland, decreasing the prolactin concentration, which also has influence on male fertility (102). Cadmium is widely used in industry, which is the main source of occupational exposure. Additional sources are a contaminated environment, food and daily consumer products, as well as tobacco smoke (34). The daily diet intake amounts to about 1 µg/day, while tobacco smokers provide an additional 1 – 3 µg daily (103). This has been confirmed in studies that showed higher (statistically significant) concentrations of cadmium in the blood of smokers than nonsmokers. A significant positive correlation was found between cadmium blood levels, number of immotile spermatozoa, and theratozoospermia index (TZI) (104). Cd exposure affects human male reproductive organs/system and deteriorates spermatogenesis and semen quality, especially sperm motility and hormonal synthesis/release. Exposure to Cd at low doses has adverse effects on both human male and female reproduction and affects pregnancy or its outcome (105). In addition to chromium, Cd is the best known and most often examined ME for hormonal activity. Cadmium has been shown to activate the ERa receptor by interactions with the LBD region, probably by replacing the zinc ions in the area of the so-called zinc finger motif. Although the precise mechanism by which cadmium activates ERa remains to be defined, it is possible that interaction of the metal with amino acids located on helices H4, H8, and H11, and at the interface of the loop and helix H12 in the ERa receptor structure, induces structural changes that mimic the structural changes induced upon the binding of estradiol. Activation of the receptor leads to the expression of estrogen-regulated genes and consequently an estrogenic effect without the presence of the natural hormone (106). Ren et al. (107), to clarify the molecular mechanism of Cd-induced toxicity in testes, compared metallothionein (MT) gene expression, MT protein accumulation, and Cd retention at different times in the freshly isolated testicular interstitial cells and liver of rats treated with Cd. They revealed that Cd exposure substantially increased hepatic MT (3.9-fold increase), but did not increase MT translation in interstitial cells. The authors concluded that the inability to induce the metal-detoxicating MT-protein in response to Cd, may account for a higher susceptibility of testes to Cd toxicity and carcinogenesis, compared to the liver.
A direct effect on the induction of reactive oxygen species by Cd has not been demonstrated. However, it has been shown that by binding the sulfhydryl groups of glutathione (GSH), cadmium may indirectly exacerbate the OS (108). In mouse studies, statistically significant lower antioxidant enzyme activity of CAT, SOD and peroxidase (POD) compared to the control group, after intraperitoneal administration of cadmium chloride (1 mg/kg b.w.), was demonstrated (109). Other animal studies also point to increased OS, decreased expression of testicular antioxidant enzymes, sperm motility and sperm count after the intraperitoneal administration of cadmium acetate at a dose of 0.025 mg/kg b.w. For 15 days (110, 111). Reduced activity of steroidogenic enzymes 3β- and 17β-hydroxysteroid dehydrogenase has also been noticed, which may contribute to the disturbance of T synthesis and thus promote disorders of spermatogenesis. Additionally, coexposure to Cd and Pb showed more toxic effects to Cd exposition than Pb, while combined exposure demonstrated least toxicity (107). Metal-exposed groups showed significantly decreased testicular and epididymal sperm counts (112). Antioxidants such as vitamin C prevent changes in the activity of these enzymes caused by cadmium. This indicates a significant effect of ROS on spermatogenesis processes (110).
Examination of the toxic effects of cadmium on somatic cells in mammalian testes showed that the blood-testes-barrier (BTB) was particularly sensitive to cadmium. In in vitro studies of Sertoli cell cultures, it was shown that cadmium is affected by tight cell-to-cell junctions, probably via specific signal transduction pathways and signaling molecules, such as p38 mitogen-activated protein kinase (MAPK) (103). Other studies have also shown damage to seminiferous tubules by cadmium chloride, resulting in the exfoliation of immature germ cells in the lumen of the seminal tubules and inhibition of the proliferation of piglet Sertoli cells (113). In rat studies it was shown that doses of 30 mg/L Cd administered orally for 90 days showed effects on sperm motility and abnormal percentages of sperm, which were significantly lower when compared to the control group. The percentage of motile spermatozoa and morphologically normal sperm was markedly reduced (114). In a cross-sectional study in the Chinese population, the concentration of cadmium in urine and semen samples of men from the Reproductive Center of Tongji Hospital in Wuhan was examined. It was shown that urinary levels of cadmium were significantly negatively correlated with progressive sperm motility and total motility. Environmental exposure to cadmium, as well as other metals (molybdenum and lead) significantly contribute to a decline in human semen quality (115). Similar results were obtained by De Franciscis et al. (104), who measured cadmium concentration in the blood and semen samples of healthy males. A significant correlation between blood cadmium concentrations, cigarette smoking, occupational exposure, and parameters of semen quality (number of non-motile spermatozoa, theratozoospermia index) was observed. The authors concluded that such a reduction in spermiogenic function could be an early marker of a toxic effect of cadmium pollution.
Famurewa and Ugwuja (116) showed that cadmium in seminal and blood plasma, as well as lead in blood plasma, were significantly higher in azospermic and oligospermic men compared to normospermic men. However, while seminal plasma lead was significantly higher in oligospermic and normospernic men than in azospermic men, the seminal plasma lead was comparable between oligospermic and normospermic men. They found significant inverse associations between blood and seminal cadmium levels and sperm count, motility and morphology, but blood lead was inversely correlated with sperm count only. The study suggests that environmental exposure to cadmium and lead may contribute to the development of poor sperm quality and infertility in men of reproductive age in Nigeria (116). Davar et al. (117), in their clinical study, reveal that infertile smokers had disturbances in sperm morphology, namely defective sperm heads, mid, and tail pieces, with high slow motile sperm cells. Therefore, they rely on artificial conception methods, namely in vitro fertilization and gamete intra-fallopian transfer, however these procedures in most cases result in abnormal foetal shape (117). Ranganathan et al. (118) in their study also documented that the levels of cigarette toxicants (including Cd) in semen were high, accompanied by low levels of anti-oxidants in the seminal plasma of infertile smoker subjects. In addition the investigation of Cd treated sperm cells through a scanning electronic microscope showed mid piece damage to spermatozoa. Dispersive X-ray analysis to identify the elemental composition further confirmed the presence of Cd. Finally, the in-silico analysis on semenogelin sequences revealed the D-H-D motif which represents a favourable binding site for Cd coordination. These studies clearly indicated the influence of Cd on ROS, leading to impaired sperm morphology, leading to male infertility (118).
Recently, Huang at al. (119) examined the impact of some metals, such as Al, Cd, Cr, Mn, Ni, Pb, Se and Sb, in coexposition to environmental particulate matter < 2.5 µm in aerodynamic diameter (PM2.5), on the male reproductive health of a Chinese population. The authors revealed that an increase in PM2.5 exposure was significantly associated with an 8.5% and 8.1% decrease in sperm concentration and total sperm number, respectively. They also documented that antimony, cadmium, lead and nickel exposures were significantly associated with decreased sperm concentration. Huang at al. (119) concluded that PM2.5 and certain constituents may adversely affect semen quality, especially sperm concentration, and provide new evidence to formulate pollution abatement strategies for male reproductive health.
Chromium
Chromium (Cr) is widely present in the environment. Its toxicity depends on the valence. The IARC classifies chromium (VI) as a proven human carcinogen. Chromium (III) is a cofactor of many proteins with enzymatic activity, fats and carbohydrates. It is delivered mainly with the diet, or dietary supplements. Daily intake is approximately 40 – 240 µg/day (120, 121). Exposure to hexavalent chromium refers primarily to people with occupational exposure. It gets into the organism primarily through the respiratory tract. The influence of chromium (VI) on the development of lung cancer and other respiratory system cancers has been proven (122). It has been also shown that small reproductive organs are the target organs for chromium action (123). Chromium compounds are able to generate free radicals, which have an indisputable role in carcinogenesis. Their role in the development of hormone-related diseases such as breast cancer is also well documented. Especially interesting is the interaction of estrogens with chromium as environmental toxins in free radical generation, which participates in cancerogenesis (121, 124).
The carcinogenic effect of chromium (VI) is primarily due to its significant oxidoreductive properties. A high ability to induce OS may also be related to the toxic effects of chromium on reproduction (125). It has been proven that chromium deficiency can also negatively affect semen quality in animals and humans. In research conducted by Horky et al. (126) it was noticed that a group of animals (boars) supplemented with chromium picolinate had significantly less disturbances in ejaculate parameters (sperm motility, ejaculate volume, sperm concentration and percent of pathological sperm) than the control group (receiving only 31% of the daily demand for chromium in the diet). But the vast majority of studies indicate excessive exposure to chromium and the associated OS as the cause of male fertility disorders, for example by inducing changes in sperm morphology and causing spermatogenesis disorders, as was shown in workers exposed in different occupational settings around the globe. Higher levels of chromium (VI) exposure in the workers of some occupational settings enhance the OS, which may cause cellular and molecular damage such as genotoxicity and chromosomal aberration formations, as well as carcinogenic effects (125). Bassey et al. (127) showed that the mean seminal plasma chromium level (measured by Atomic Absorption Spectrometry) of oligospermic and asthenooligospermic patients was significantly higher in infertile men than in healthy, fertile men. The authors conclude that this high chromium concentration has adverse effects on sperm production, motility and sperm count in infertile men.
In mouse studies, increased concentrations of OS parameters in the testes was observed, as well as significantly decreased sperm count and markedly increased rates of sperm abnormality after a single intraperitoneal application of chromic acid (CrO3) in a dose of 1 mg/kg b.w. (128). Similar results were obtained in studies on monkeys administered orally by potassium dichromate at concentrations of 50 – 400 ppm in drinking water. There were definitely lesser sperm counts and sperm forward motility. Additionally, the activity of antioxidant enzymes were reduced, in a dose- and duration-dependent manner. Simultaneously the administration of vitamin C significantly prevented the above-mentioned changes (129). Geoffroy-Siraudin et al. (130) developed the special experimental model (culture of rat seminiferous tubules) examining the exact key phases of spermatogenesis (mitosis, meiosis and the initial stages of spermiogenesis), which are disrupted as a result of Cr(VI) action. The authors revealed an increasing amount of abnormal nuclei in a dose-dependent manner, which indicates that chromium compounds have an effect on prophylaxis and meiosis. Some studies also examined toxic testicular damage by Cr(V), which is generated as an intermediate metabolit from the intracellular reduction of Cr(VI), and is also indicated as an agent of carcinogenesis. The subcutaneous administration of Cr(V) complex ([CrV-BT]2) into mice induced impaired permeability of the BTB, as was confirmed by histochemical examination of isolated seminal ducts. Significant damage to Sertoli cells and germ cells, and irregular spermatoid features, as well as statistically significant reductions in acrosome integrity, were observed (131). In the light of an increasing number of used metallic nanoparticles and ions from cobalt-chromium (CoCr) alloy prosthesis, potential adverse effects were revealed, however, their biological effects on male reproductive function remain unclear. Examination of their effect on adult male rat reproduction after intraarticular injection of CoCr nanoparticles at doses of 20 – 500 µg/kg b.w. for 10 weeks revealed dose-dependent decreased sperm motility, number and viability. High doses of nanoparticles, especially, could significantly reduce epididymal sperm motility, viability and concentration, increase abnormal sperm rate and levels of Co and Cr ions in serum and in the testes, as well as induce testicular damage and pathological changes via OS (132).
Chen et al. (133) evaluated the influence of metal ion exposure on semen quality in young male patients undergoing total hip arthroplasty using metal-on-metal (MoM) articulations. Patients were sorted into MoM and metal-on-polyethylene (MoP) groups with equal case numbers. Compared to a preoperative baseline, patients in both groups had increased cobalt and chromium concentrations in the blood and seminal fluid after surgery. Between group comparisons at 6 months and 1 year after surgery showed that patients in the MoM group both had greater Co concentrations in blood and semen and greater Cr concentration in blood and semen. Patients receiving MoM prosthesis had a reduced percentage of morphologically normal sperm, and decreases from the preoperative level (44.7%) were significant at 6 months (36.8%) and 1 year (33.8%). The authors concluded that their data shows a significantly greater concentration of metal ions in the blood and semen in patients with MoM prosthesis with a reduced percentage of morphologically normal sperm. However, despite small effects on sperm quality, some concerns remain (133).
Cobalt
Another important micronutrient is cobalt (Co), which is a key element of cobalamin (vitamin B12). Daily dietary intake ranges between 5 and 50 µg/day (134). Although it is not a cumulative toxin, chronic exposure induces negative effects on the organism (135). A mouse study revealed that exposure to cobalt during the perinatal and postnatal period affected body weight during puberty, but did not significantly reduce reproductive organ growth. However, the negative impact of cobalt on later life cannot be ruled out, and cobalt might be considered as a possible risk factor for male reproductive health (136). In studies on male Swiss mice exposed to (CoCl2×6H2O) in drinking water for a period of 12 weeks, a significant reduction in the number of fertilizations was demonstrated when pairing with non-exposed females at a dose of 400 ppm and 800 ppm. Histopathological examination showed seminiferous tubules and interstitial tissue necrosis, Leydig cells hypertrophy and spermatogonial cell degeneration. The authors also noted a decrease in epididymal weight at a dose of 800 ppm, a decrease in epididymal sperm count in three doses: 200, 400 and 800 ppm, as well as a reduction in daily sperm production in two doses: 400 and 800 ppm (137).
The studies of Zeng et al. (138) have shown that urinary metal concentrations directly or indirectly influence circulating testosterone production in Chinese men. Urinary concentrations of some selected metals (e.g. arsenic, cadmium, cobalt, chromium, copper, lead, molybdenum, mercury, nickel, selenium and zinc) and serum levels of T were analyzed in men from an infertility clinic. Among the measured metals, the median urinary Zn (359.36 µg/g creatinine) and Co (0.16 µg/g creatinine) concentrations were the highest and lowest, respectively. Significant dose-response relationships were found between decreased T and urinary Mn and Zn, even when considering multiple metals. The authors concluded that elevated Mn and Zn are inversely associated with T production.
Marzec-Wroblewska et al. (31) analyzed cobalt (Co), chromium (Cr), and lead (Pb) concentrations in human semen and catalase CAT activity in seminal plasma, and the effects of their relations on sperm quality. They examined the relationships and differences between Co, Cr, and Pb concentrations in seminal plasma, CAT activity, and semen parameters. The authors did not establish differences in Co, Cr, and Pb concentrations or CAT activity between normozoospermic men and those with pathological spermiogram. However, they found significantly lower Co concentrations and CAT activity in males with normal sperm motility than in asthenozoospermic males. They found significantly lower Co and higher Pb concentrations in males with normal morphology of spermatozoa than in theratozoospermic males. There were significant correlations between Co and Pb concentrations, sperm progressive motility, and normal morphology of spermatozoa (Co-negatively; Pb-positively). A significant negative correlation between Cr concentration and slow progressive motility, and between CAT activity and volume of ejaculate. Co, Cr, and Pb levels and CAT activity were also related to sperm characteristics and male fertility. Co and Pb influence progressive motility and normal morphology of human spermatozoa. Marzec-Wroblewska et al. (31) concluded that Co and Pb levels in semen may be a useful diagnostic in male infertility.
Copper
Copper (Cu) is an extremely important microelement in humans and plays a significant role in the metabolism. It occurs in many enzymes as an essential element to their action. Among others, Cu is a part of cytochrome C oxidase, a key enzyme catalyzing the final step in the mitochondrial electron transfer chain, but also SOD. Depending on the concentration, copper may reduce or induce OS, which seems to be a very important aspect of its action in the cells. Its protective role is connected with the fact that Cu is an element of the active center of SOD-1 (52). Tsunoda et al. (139) showed that deficiency of SOD-1 causes a decrease in in vitro fertilization ability by intensifying OS, reducing ATP levels and causing disorders of the tyrosine phosphorylation process. It also had a negative effect on sperm motility in tested mice (Sod1-KO sperm in compared to wild-type sperm). Cytochrome C oxidase is a key enzyme responsible for normal sperm motility, through its role in the ATP production. The occurrence of a specific cytochorm C isoform in the male gonadal cells, isoform VIb-2, has been reported (140).
In the organism, copper metabolism is primarily associated with the ceruroplasmin, and it was shown that within the testes, approximately 80% of seminal ceruloplasmin is located in the Sertoli cells. Its direct or indirect impact on the structure and function of male gonads and gametes is not yet completely understood. It also concerns iron ions, which together with Cu, are essential trace nutrients also playing important roles in human health and fertility. Excess or deficiency of either element may lead to defective spermatogenesis, reduced libido, and oxidative damage of the testicular tissue and spermatozoa, ultimately leading to fertility impairment (141). Another important protein that helps maintain copper homeostasis in the organism is metallothionein. The metallothionein isoform (MT-1) is found in Sertoli cells and in spermatogenic cells, which indicates the important protective function of MT-1. The existence of this isoform was demonstrated in rat studies where significantly higher MT-1 mRNA expression was demonstrated after subcutaneous cadmium injection (142). Moreover, metal replacement studies using an apo-polypeptide of the estrogen receptor DNA-binding domain demonstrated that copper binds to the ER-DBD with greater affinity than does zinc, confirming its action as a metalloestrogen (143).
Copper action as a ME was showed in animal and cell model studies (75). In human studies, a significant negative correlation between Cu concentration in seminal plasma and percentage of sperm with normal morphology was demonstrated. The control group consisted of males exposed to copper as a result of local contamination from the e-waste factory. The concentration of copper and other metals (Cr and Cd) was statistically higher than in the control groups, made up of residents of cities distant by 100 km (group 1 control) and 200 km (group 2 control) from the contamination area (144). In research conducted by Li et al. (145) a significant negative correlation between Cu and sperm concentration and motility was also found in Chinese men. Almost half of the tested men had decreased fertility (based on sperm count and motility). The level of copper in the semen of these males was statistically higher than in the group with normal semen parameters. Some studies showed lower seminal plasma Cu level in azoospermic males compared to healthy controls, leading to a concomitant decrease in SOD activity and a higher risk of oxidative stress (146).
Recently Palanil et al. (147), determining the relationship of the concentration of some metals (among others copper, lead, chromium, selenium) present in seminal plasma with semen parameters and reproductive endocrine function in men in and around Chennai (India), found that the most affected age group was 31 – 40. The mean value of the levels of the examined metals present in seminal plasma were significantly higher in azoospermia, asthenozoospermia, asthenoteratozoospermia, oligoasthenozoospermia and oligoasthenoteratozoospermia participants, when compared to normozoospermia participants, and showed adverse effects on male infertility. Additionally the authors concluded that lifestyle changes and associated factors have a high impact on the incidence of male infertility among and around the Chennai population.
Lead
Lead (Pb) shows well known significant toxicity for living organisms. It has neurotoxic and nephrotoxic effects, and causes damage to bones, digestive and immune systems. The main route of exposure is the alimentary route, but occupational exposure by inhalation is also important (148). The concentration of Pb in exposed workers should not exceed 30 µg/dL, while the permissible level for unexposed adults should be lower than 25 µg/dL. Lead has a high capacity for accumulation in the organism, and also in the male reproductive system, especially in the epididymis, prostate, seminal fluid and vesicular seminalis, which may explain the damage to sperm motility. Leydig cells are particularly susceptible to lead, which contributes to impaired T synthesis and consequently to disorders of spermatogenesis (149). Pb preferentially accumulates in male reproductive organs and can be up to 10 µM in human seminal plasma, and impairs mammalian spermatogenesis and sperm quality in vivo. It also inhibits sperm functions in vitro, but the underlying mechanisms remain unclear (150). Sperm motility and sperm morphology are considered to be particularly sensitive to lead influence. This was confirmed in a study, in which rats were treated orally by lead acetate (6 mg/kg) for 8 weeks. Significantly smaller sperm counts, decreased motility and abnormal sperm morphology (expressed as percentage of sperm with abnormal morphology) were noticed. Also, increased oxidative stress has been demonstrated, expressed as: reduced level of GSH, increased hydrogen peroxide (H2O2) and LPO (lipid peroxidation products) in nuclear tissue homogenates, indicating the ability of lead to induce OS in infertile men (151). In other studies conducted on male mice divided into 3 groups: an untreated group, a low-dose group (50 µg/kg b.w.) and a high-dose group (100 µg/kg b.w.), received lead acetate in drinking water for 16 weeks, and a statistically significant increase in the percentage of immobile sperm in the treated groups was observed, when compared to the control group. Significant reduction in the number of live sperm in both doses of Pb and mean sperm concentration in the high-dose group was also noticed. The amount of immotile sperm, the percentage of DNA fragmentation and the percentage of sperm degradation also significantly increased. The most common type of sperm degradation was sperm with a small halo, as was shown by sperm chromatin dispersion (SCD), the method used for detection of sperm DNA fragmentation, however, no significant differences were noticed between analysed groups (152).
Some authors showed an increased amount of agglutinated sperm in infertile men, and indicated that agglutination may be related to the effects of anti-sperm antibodies. This phenomenon is favored by damage to the testes structure under the influence of lead salt, among others BTB. Excessive agglutination may cause the reduction of sperm motility (153). No impact on the integrity of BTB, however, was observed in human studies, which could be explained by the lack of influence of spontaneous acrosomal reactions, which are not induced by Ca2+ ions. In Chinese men a broad range of lead acetate concentration (0 – 100 µM) inhibits human sperm functions by reducing the levels of sperm intracellular cAMP, [Ca(2+)i] and tyrosine phosphorylation of sperm proteins in a dose-dependent manner (150). Some authors suggest the influence of lead on chromatin condensation processes during spermatogenesis, by zinc replacement from protamine binding sites, reduction of chromatin stability and as a result reduction in sperm quality (154).
Studies on an animal model (crab Sinopotamon henanense) exposed to lead indicate that this metal probably disturbs calcium homeostasis through interaction with calcium channels (as indicated by experience with verapamil-calcium channel blockers, compared to controls). Exposure of Pb tested animals caused a decrease in acrosomal response, increased oxidative stress (increased protein carbonylation (PCO) and malonyldialdehyde (MDA) concentration), weaker integration of sperm DNA and reduced viability of sperm. Under the influence of lead, the intracellular concentration of calcium and activity of acrosine decreased, and the activity of calmodulin was reduced (calcium ions are required to activate calmodulin and change its conformation) (155). Similarly, the impact of lead, as well as cadmium, on seminal parameters in idiopathic oligoasthenozoospermic infertile males was observed. Pb reduces the mobility of sperm and progressive motility and, importantly, significant positive correlations were observed between seminal lead and cadmium levels and percentage of sperm DNA fragmentation, and semen ROS level in infertile men (156). In He et al. (150) in vitro studies, samples of human semen were exposed to various lead acetate concentrations. They revealed that treatment with 10 – 100 µM lead acetate reduces sperm mobility in a dose-dependent manner, and also managed to slow down capacitation and acrosomal response. Decreased motility may be caused by a decrease in the intracellular concentration of the cAMP - the second intracellular messenger (by inhibition of adenylyl cyclase), as well as by reduction of intracellular Ca2+ ion levels, and inactivation of tyrosine kinase, which may result in effects on sperm function (150). Pant et al. (157) showed that semen lead and cadmium values were significantly higher in infertile subjects. A negative association between concentration of these metals and sperm concentration, sperm motility and percentage of abnormal spermatozoa was found. Authors showed that exposure to Pb and cadmium in environmental concentrations might affect the semen profile in men. Additionally, age, diet, smoking and tobacco chewing habits may have an influence on the increase in exposure to Pb and Cd in the individual subjects.
Molybdenum
Molybdenum (Mo) although is one of the least common elements on Earth, plays an important role in the proper functioning of the human organism, being among others a cofactor of many enzymes. It is a microelement which is the active center of about 50 enzymes, including xanthine oxidase and aldehyde oxidase, and it is also a catalyst for redox reactions in the body. The daily requirement is set at 100 – 300 µg/day (158). The main route of exposure to this metal is oral absorption. It is also used in various industries, which cause excessive exposure to this element. The role of Mo as a xenoestrogen has been described, but the exact mechanism of the harmful effects of molybdenum on male reproduction is unknown and data are not uniform (34).
In studies on the development of mouse embryos, preimplantation cultured in vitro, exposed for 5 days of sodium molybdate at a different doses (from 0 to 160 mg/mL), a dose-dependent negative effect was revealed. No negative effects were observed at small doses, but at doses of 40 µg/mL and higher, the cleavage of blastocyst and delivery birth rates significantly decreased, and a significantly increased proportion of degenerated blastocysts were revealed (159). This was confirmed in studies on mice, during 14 days of oral molybdenum administration with water (in the form of sodium molybdate dihydrate) at different doses (from 0 to 200 mg/L). It was shown that molybdenum in smaller doses of 25 mg/L improved the sperm quality of the tested mice, but at the lowest doses did not show any effect. However, in higher doses, a significant negative effect was noted on the epididymis index, sperm motility, concentration and abnormality rate. Additionally, reduced activity of SOD and GPx, as well as increased MDA concentrations, have been shown, which may indicate increased OS, especially at the highest doses (160). In experimental studies with rabbits fed commercially available food contaminated with molybdenum, an increased number of abnormal spermatogenic cells of seminiferous tubules and large sized syncytial cells were found, while the number of mature spermatocytes decreased significantly. The generation of free radicals, due to the high dietary Mo intake, resulting in a marked increase of creatine kinase (CK) activity was indicated as the main way of action (161). Whereas in a multigenerational study of rats exposed to molybdenum in the form of dihydrate (0.5 – 40 mg/kg b.w./day) for a period of 90 days, no changes in sperm parameters in the male subjects were observed. Additionally, the value of the NOAEL (No Observable Adverse Effect Level) for reproductive toxicity (gonadal, sperm and estrus cycle effects) was established at 60 mg Mo/kg b.w./day, and at 17 mg Mo/kg b.w./day for systemic toxicity (162).
In cross-sectional observational data conducted by Zeng et al. (163) on Chinese men, patients at an infertility clinic, and the influence of 13 different metals (As, Cd, Co, Cr, Cu, Fe, Pb, Mn, Mo, Hg, Ni, Se, Zn) on parameters reflecting semen quality (sperm concentration, count, motility, normal morphology, and abnormal head) did not show any correlation between Mo concentration in urine and decreased semen quality, but potential adverse exposition to nickel and selenium was indicated. The authors suggest that further epidemiological studies were needed to obtain data on long-term exposure to these metals. Somewhat different results were obtained by Meeker et al. (164), who examined the urinary levels of 18 different metals, including essential and nonessential elements (among others As, Cd, Cr, Cu, Pb, Mn, Hg, Mo, Se, Zn) in infertile men regarding their connection with semen quality parameters. The authors suggest that environmental exposure to molybdenum, cadmium and lead may significantly contribute to a decline in human semen quality, however they concluded that further research is needed in order to obtain knowledge about the exact mechanism of molybdenum toxicity (164).
Recently, attention has been paid to nanomaterials (nanotubes, nanowires, fullerene derivatives (buckyballs), and quantum dots), which can be also considered as a source of toxicants, due to the lack of information concerning their impact on human health and the environment. Studies on the cell lines of mouse spermatogonia showed a concentration-dependent toxicity for all types of particles tested, whereas the appropriate soluble salts had no significant effect (165). Additionally, results demonstrate cell membrane dysfunction after exposure to 5 µg/mL and 10 µg/mL of Mo, but silver nanoparticles were the most toxic, while molybdenum trioxide (MoO3) nanoparticles were the least (166). Molibdenum, in addition to cobalt and chromium, is a component of stainless steel intramedullary nails (IMN). Studies conducted by Elsamanoudy et al. (167) among men with IMN showed a statistically significant inverse relationship between the concentration of these metals in seminal plasma and sperm parameters (progressive motility, concentration and morphology). Additionally, a statistically significant decrease in Bcl-2 spermatozoal expression (antiapoptotic protein), a higher Bax expression (proapoptotic protein) and lower Bcl-2/Bax ratio in subjects with IMN for ≥ 5 years than in controls were observed. The authors indicated that spermatozoal Bcl-2/Bax ratio could be used as a candidate biomarker of reproductive disorders in individuals with IMN (167).
Mercury
The influence of mercury (Hg) on human fertility has been studied for a long time. In 1985, Lauwerys et al. (168) assessed the fertility of male workers exposed to mercury vapor or manganese dust. Hg concentration in the urine of employees was determined, and survey data on the number of offspring was collected. In the range of Hg concentrations: 5.1 to 272.1 mg/g creatinine, obtained during the study of workers, the significant difference between the number of observed children and a well-chosen control group, which was expected based on reproductive experience, did not appear. However, such dependence was observed for exposure to manganese vapors. On the contrary Keck et al. (169) studied a 25-year-old man with unexplained infertility, who had been employed in a chemical factory and exposed for 5 years to chloralkali-electrophoresis, and revealed high mercury concentrations in hair, blood, and urine samples, considerably above the levels of unexposed controls. Semen analysis of these patients showed azoospermia or severe oligoasthenotheratozoospermia, with elevated serum FSH levels. The toxic action of Hg was confirmed by autometallographic analysis of the bilateral testicular biopsies, which revealed silver-enhanced mercury grains, primarily in the interstitial Leydig cells. In a case-control study Choy et al. (170) showed that higher seafood consumption was associated with elevated blood mercury concentrations, which are connected with male and female infertility. The above observation was confirmed in animal studies. Significant adverse effects were noted on male rat reproduction endpoints, including fertility (time to impregnate the females and a lower rate of impregnation), as a result of exposure to HgCl2, even at a dose that was not clinically toxic. Additionally, a lower correlation between testicular T levels and subsequent exposure days, as well as a lower sperm count in the epididymis head and body of the exposed males was documented (171). In another cross-sectional study the influence of environmental mercury exposure on semen quality and reproductive hormones in men living in the Greenlandic Inuit, and a European region (Poland and Ukraine) were not exactly confirmed. No significant association was found between blood concentrations of mercury and the characteristics of semen parameters (semen volume, total sperm count, sperm concentration, morphology and motility) and reproductive hormone levels (free androgen index (FAI), FSH, LH, T) in any region (172).
Nickel
Due to the wide use of nickel (Ni) in industry, it is a widespread element in the environment. It has also been proven that nickel accumulates in the testes. Its toxicity has been identified in animal studies, for example in rats, where the effect of nickel exposure in the form of nanoparticles given orally has been examined (173, 174). The effect of nickel on sperm motility has been demonstrated, and a significant reduction in FSH and T levels in male rats was noted (175). Histopathological examination also revealed pathological changes in the testes (immature germ cells in the lumen of seminiferous tubules, epithelial cell shedding and abnormal cell distribution in the seminal tubule), and intensification of the apoptosis process in the group of animals treated with nickel (173). A positive significant correlation was shown between the concentration of nickel in the blood and the percentage of tail defects in male sperm compared to the control group (176).
Zafar et al. (177) investigated a male Pakistani population and found that Cd and Ni showed significant differences among three monitored groups (normozoospermia, oligozoospermia and azoospermia). Ni and Cd concentrations in the seminal plasma were negatively correlated with sperm concentration and motility. This study suggested that exposure of Ni and Cd was mainly related to the consumption of contaminated dietary items, including ghee (cooking oil), flour and other agri-products. In some semen samples, the concentrations of Sn, V, Cu, Pb, Cr and Hg exhibited high levels, suggesting recent human exposure to surrounding sources. In Pakistani semen samples, the levels of trace metals were lower and/or comparable to those found in the populations of other countries (177). Zeng et al. (163) examine the association between urinary metal concentrations, e.g. As, Cd, Co, Cr, Cu, Pb, Mo, Hg, Ni and Se, and semen quality parameters (sperm concentration, count, motility, normal morphology, and abnormal heads) in a Chinese population. The authors suggest that, among other factors, Ni exposure may be associated with deteriorated sperm morphology, and that Se exposure may be associated with better semen quality. Zhou et al. (178) studied the associations between urinary metal concentrations and sperm DNA damage, and they found that urinary Hg and Ni were associated with increasing trends for DNA tail length, and that urinary Mn was associated with an increasing trend for DNA tail distributed moment. These associations did persist, even when considering multiple metals. Our results suggest that environmental exposure to Hg, Mn, and Ni may be associated with increased sperm DNA damage (178).
Selenium
Selenium (Se), similarly to copper, is considered an important element in maintaining the reproductive health of men, among other factors, because of its role as an antioxidant (179). It was indicated in animal studies that supplementation with Se (6 µg/kg b.w. in organic form) and vitamin E (5 mg/kg b.w.) after 60 days positively affected semen parameters in dogs: an increased percentage of sperm with normal morphology, concentration of spermatozoa, their viability and motility were noticed. The antioxidative activity in spermatozoa also increased (expressed as increased activity of GSH-Px and TAC) (180). In studies on buffalo bulls, a positive effect of selenium supplementation (10 mg Sel-Plex® twice weekly) on parameters such as percentage of viable sperm and T levels was observed, in comparison to the control group (not supplemented) (181). In studies on varicocelized male Wistar rats, the protective effect of the oral administration of sodium selenite (at doses from 0.05 to 0.4 mg/kg b.w.) on testicular damage was demonstrated. Improved parameters of sperm quality, decreased activity of CAT, GPX and SOD, increased levels of MDA, and improved damage in testicular architecture were observed in varicocelized rats, without changes in these parameters in normal rats (182). In larger quantities, however, selenium may adversely affect male fertility. Selenium negatively influences semen quality in human studies, as was shown by Wan et al. (183). The authors showed a reversed relationship between Se in seminal plasma and linear velocity (VSL), and average path velocity (VAP). Previously Saaranen et al. (184) revealed that selenium accumulates in the testes, as evidenced by the much higher level of this element in seminal plasma than in the urine of the studied men.
Hawkes et al. (185) in their study documented that Se supplementation had no effect on sperm Se, serum androgen concentrations, sperm count, motility, progressive velocity, or morphology. They observed progressive decreases in serum luteinizing hormones, semen volume, and sperm Se in both the high-Se and placebo groups. Moreover, sperm straight-line velocity and percentage of normal morphology increased in Se-treated and placebo-treated participants. The lack of increase in sperm Se suggests that testicular Se stores were unaffected, even though the participants’ dietary Se intake was tripled and their total body Se was approximately doubled by supplementation (185). Eroglu et al. (186) showed a positive correlation between serum and semen Se levels, and Se levels were found to be significantly lower in infertile than fertile men. In this study, higher levels of serum and seminal plasma Se were detected in the normozoospermia group when compared with the mild and severe oligozoospermia groups. The severity of oligozoospermia was found to increase as Se levels decreased accordingly. Additionally, levels of serum Se were correlated positively with levels of seminal plasma Se, suggesting that higher levels of Se in serum directly affect levels of seminal Se. Furthermore, a linear correlation was observed between decreasing sperm motility and decreasing levels of serum and seminal Se. These findings suggest that serum Se levels affect sperm concentration and motility. The results of Eroglu et al. (186) study suggest that low levels of serum Se accompany low levels of seminal Se, which in turn negatively affect sperm quality and lead to idiopathic male infertility. Safarinejad et al. (187) have also reported that Se supplementation increases serum and seminal levels of Se. In parallel with the results of Eroglu et al. (186) study, these findings suggest that Se deficiency in serum leads to Se deficiency in seminal plasma, causing poor sperm quality and male infertility. Another finding presented by the authors was that both serum and seminal levels of Se were correlated positively with sperm morphology (186).
Marzec-Wroblewska et al. (179) analysed sodium (Na), copper and selenium levels in human semen and GPx in seminal plasma, and examined their correlations with sperm quality. Se concentration (but not sodium or copper) and GPx activity were significantly higher in normozoospermic males than in those with a pathological spermiogram, and also in males with correct sperm motility and normal sperm morphology rather than in asthenozoospermic and theratozoospermic males. The authors observed the presence of significant correlations between sperm motility, Se and GPx, between rapid progressive motility and Cu, between sperm motility and Na, between normal sperm morphology and Se and Cu, and between sperm concentration and Cu and GPx. Moreover, they found significant correlations between Na and Cu, between Na and Se and between Cu and Se in human semen in relation to alcohol consumption and tobacco use (179).
Vanadium
Vanadium (V) is an element to which exposure mainly occurs through inhalation and the alimentary route. It is released into the atmosphere in the process of the combustion of fuels. Due to industrial development, its intake is significant, especially in some particular areas. The level of 1.8 mg/day is a tolerated daily intake and is considered an essential metal. Excessive supply of V, however, causes serious disorders associated, amongst others, with hepatotoxicity, nephrotoxicity, neurotoxicity and reproductive toxicity (188). It is believed that the above changes are mainly related to the induction of OS. This was confirmed by studies conducted on rats treated with sodium metavanadate (1 mg/kg b.w. for 90 days period). An increased testicular level of MDA as well as lower testicular SOD and CAT activity were observed, but the administration of G-hesperidin, as an antioxidant, reduced the severity of these changes. Additionally, it was shown that vanadium exposure causes a significant reduction in sperm count, viability, serum T level, and an increase in the number of sperm cells with abnormal morphology and histopathological changes in the testes as compared to the control group. It was also noted that fragmented DNA of sperm, expressed as DNA fragmentation index (sDFI), was significantly higher than in the control group. The authors indicated that vanadium exposure caused reduced bioavailability of androgens to the tissue and increased free radical formation, thereby causing structural and functional changes in spermatozoa (189).
Fortoul et al. (190) showed that inhalation exposure to vanadium pentoxide (V2O5) at 3.64 g/h for a 12-week period in the tested mice caused necrotic changes in Sertoli cells and spermatocytes, as well as changes in tight junctions in BTB (pseudoinclusions were observed). The authors indicate tight junctions as a possible point of grip for V and oxidative stress induced by V. In human studies it was demonstrated that seminal plasma vanadate levels were significantly negatively correlated with serum levels of total T and free T. There was also a significant positive correlation between seminal plasma V level and estradiol serum level. Lower hormone levels in men may be caused by damage to Leydig cells and inhibition of hormone synthesis such as: Δ53β- and 17β-hydroxysteroid dehydrogenase (HSD) as demonstrated in animal studies (191). Other in vitro and in vivo studies demonstrated that vanadium treatment resulted in a significant disturbance of oxidative/antioxidative balance. With the increase of testicular lipid peroxidation, marked lowering of SOD and CAT activities, decreased sperm count, and substantially inhibited activities of Δ53β- and 17β-hydroxysteroid dehydrogenase, as well as serum T level were observed. Importantly, all these changes were dose- and time-dependent. This suggests that during vanadium exposure testes may be more susceptible to oxidative damage leading to their functional inactivation, as was confirmed histopathologically (192).
Others
Only single sources of information are available about other metalloestrogens, and all of them are described below.
Giaccio et al. (193) in an Italian population examined the influence of heavy metal pollution (inter alia antimony - Sb) as possible candidates for influencing human semen quality, due to effects on ejaculate quality in men living in metropolitan areas, at a continued exposure to low doses. The authors revealed a strong correlation between abnormal Sb concentrations and men with poor semen quality (disturbances in semen volume, sperm concentration, sperm total count, sperm motility, pH). The results show a strong correlation between anomalous Pb and Sb concentrations and men with poor semen quality (193).
In recent research conducted by Sukhn et al. (194), it was shown that the concentration of barium (Ba) in seminal fluid is significantly higher in the group of examined men with abnormal sperm parameters compared to men with normal sperm parameters during environmental exposition to this metal. The authors found that participants with low-quality semen had significantly higher Cd and Ba concentrations in the seminal fluid than participants with normal-quality semen. They also observed significant associations between low sperm viability and higher blood Cd and Ba. The authors concluded that in non-occupationally exposed men, measurements of heavy metals in the seminal fluid may be more predictive of below-reference sperm quality parameters than in blood (194).
Information about tin (Sn) is provided by the study conducted by Guzikowski et al. (175), who revealed significant correlation between Sn level in seminal plasma and sperm count of men living in infertile couples. There was also a statistically significant difference between the concentration of Sn in seminal plasma in two subgroups: men with reference semen parameters and men with low semen quality. The exact mechanism of Sn reproductive toxicity is not yet known. Ghaffari et al. (195) examined in vitro effects of few metals (e.g. Hg, Pb, Sn) on sperm creatine kinase activity, and revealed that this studied metal ions (at levels of 60 mg ml-1), may reduce normal sperm metabolism by inhibition of sperm creatine kinase, which probably is an important cause of infertility in men. Guzikowski et al. (175) found that tin and cadmium levels were correlated with sperm count, but not with sperm motility and morphology in ejaculates of men with limited fertility potential. Additionally the significant differences between infertile and normozoospermic groups for cadmium and tin levels in semen were observed (175). Wang et al. (196) showed that environmental exposure e.g. to tin, nickel and molybdenum may be associated decreased total T or total T/LH ratio. They found significant inverse dose-dependent trends of urinary tin quartiles with total T, as well as tin, nickel and molybdenum with the ratio of total T/LH ratio, but there were no significant associations between urinary metals and sperm DNA damage (196).
Conclusions
In the XXI century exposure to metals is a very serious problem in highly developed countries mainly due to their wide use, as well as their long half-life and also their ability to accumulate in the organism. Despite the well-known harmful effects of such elements as e.g. cadmium or lead on many organs, further research is still needed to explore the detailed mechanisms of their action on the physiology of reproductive organs. Many metalloestrogens exert a wide variety of adverse effects on reproduction and development, including influence on male subfertility or fertility. Their action depends on several factors, such as timing and duration of exposure, distribution and accumulation in various organs, and on interference with specific developmental processes.
This study is an attempt to systematize knowledge about the role of metalloestrogens on male fertility, particularly current knowledge concerning environmental factors. Not all studies can be performed on humans, therefore animal models and cell culture investigations are very helpful for understanding the molecular mechanisms of xenoestrogens actions, reflecting their possible influence on the human organism. The mechanism of the action of metals is diverse, but due to the possibility of influence on the estrogen receptors’ function they are commonly called metalloestrogens. Some of them can exert effects over the estrogen receptors, but not all, and many metals were not even investigated. Others act indirectly by modulation of estrogen receptors in different ways, but the mechanism of action of others is mainly related to ROS generation and OS induction. They can influence male fertility on many levels. An interesting, but still not well-studied area, is the examination of possible interactions between individual metals and estimation of their actions, especially at lower concentrations, because most studies concern exposition to high levels of metals. Additionally, a polymorphism of genes encoding some proteins with enzyme activity (e.g. metal ions as cofactors) or proteins transporting some metal ions (e.g. metallothionein) is worthy of further investigation. The mechanisms of action of most metalloestrogens on male reproductive health seem to be similar and common to all of those described in our review. This is also indicated by a study conducted by various research teams, analyzing panels of many xenoestrogens in parallel. Awareness of the effects of these toxic ubiquitous metals on male reproduction is important, but further studies are required to expand our basic knowledge, resolve inconsistencies, and assess the consequences on male fertility of exposure to metal ions, especially concerning the effects of low exposition, which is more often observed in daily life.
Due to the fact that many studies are available in various databases on the effects of xenoestrogens’ action on male fertility, and new reports are constantly being published, we decided to limit the number of those analyzed, taking into account that it is not possible to analyse and include all the available information. An additional limitation of this study is the lack of detailed statistical analysis of the collected literature data, so further meta-analysis will be interesting and helpful in understanding the impact of xenoestrogens, both environmental and occupational, which will enable the introduction of the appropriate preventative strategies, to avoid these harmful actions.
Authors’ contribution: All authors participated in developing of the conception, contributed to writing the manuscript and gave their final approval of the submitted version.
Acknowledgements: This work was supported by the Wroclaw Medical University under Grant - ST.D180.18.004 and ST.D160.18.009.
Conflict of interests: None declared.
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A c c e p t e d : June 28, 2019